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From the Andrology and IVF Laboratories, Departments of Surgery (Urology), Obstetrics and Gynecology, and Physiology, University of Utah School of Medicine, Salt Lake City, Utah.
| Correspondence to: Dr Douglas T. Carrell, Andrology and IVF Laboratories, 675 S. Arapeen Dr, Suite 205, Salt Lake City, UT 84108 (e-mail: douglas.carrell{at}hsc.utah.edu). |
| Received for publication July 18, 2007; accepted for publication September 5, 2007. |
Severe male infertility has been shown to be associated with improper
meiotic recombination and elevated sperm chromosome aneuploidy. Elevated sperm
aneuploidy increases the risk of embryo lethality or fetal anomalies. Although
difficulties in interpreting aneuploidy data still exist, advances in
fluorescent in situ hybridization (FISH) technology have facilitated the study
of sperm from patients with severe spermatogenesis defects, which has
demonstrated the prudence of evaluating sperm chromosome aneuploidy in men
with severe male factor infertility, such as nonobstructive azoospermia or
severe ultrastructure defects, especially in cases of previous repeated in
vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failure.
Testing is also advisable in men with chromosome translocations and
unexplained recurrent pregnancy loss, and it may be beneficial in patients
with unexplained, repeated IVF failure. Automated FISH imaging and analysis
technology is now available and is beneficial in reducing technician time
analyzing sperm aneuploidy. Emerging technologies, such comparative genomic
hybridization, may be beneficial in further improving the quality of data
derived from aneuploidy analysis and reducing the cost of the assay.
Key words: FISH, meiotic recombination, chromatin
Intracytoplasmic sperm injection (ICSI) has facilitated fertilization in cases of extreme spermatogenesis defects, which is both beneficial to infertility patients and the cause of heightened concern about the possibility of increased genetic risk, including the potential of an elevated risk of embryo aneuploidies (Verpoest and Tournaye, 2006; Tesarik and Mendoza, 2007). Indeed, it does appear that there is an increased risk—as much as threefold—of sex chromosome aneuploidies in the offspring of men with severe male factor infertility treated by ICSI (Rimm et al, 2004; Hansen et al, 2005; Ludwig, 2005). Therefore, it is important to understand whether certain sperm pathologies may be associated with an increased risk of sperm chromosome aneuploidy, if the increased risk can be ascertained prospectively, and if such information can be used to better assess the risks and potential of success of IVF for patients (Petit et al, 2005; Faure et al, 2007).
Fluorescent in situ hybridization (FISH) technology has greatly expanded our ability to study sperm chromosomes. However, technologic limitations, costs, and limits in our ability to translate the results of sperm aneuploidy to actual risk to offspring have all contributed to a decreased clinical utility of sperm chromosome aneuploidy testing. This review briefly traces the history of sperm aneuploidy testing, highlights recent technologic advances, discusses our current understanding of sperm chromosome aneuploidy, and considers the future clinical use of sperm chromosome aneuploidy testing.
Technological Advances in Sperm Chromosome Aneuploidy Testing
Sperm/Oocyte Fusion Technique—
In 1978, Rudak et al published the first account of the evaluation of sperm
chromosome abnormalities (Rudak et al,
1978). Sperm were evaluated from 1 patient by modifying the
zona-free hamster oocyte/human sperm penetration assay system previously
developed in by Yanagimachi and coworkers
(Yanagimachi et al, 1976).
Briefly, capacitated sperm from a fertile male were incubated in vitro with
zona-free hamster oocytes, followed by further incubation of the oocytes and
treatment with medium containing colcemid to arrest metaphase-stage pronuclei.
The pronuclei then were fixed and stained using standard karyotype techniques
to allow the analysis of structural and numerical abnormalities
(Figure 1). A total of 60 sperm
were evaluated from a healthy donor, with 5% of the sperm containing an
aneuploid complement of chromosomes (Rudak
et al, 1978).
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Despite the technical difficulties involved with the assay, a few other laboratories were able to employ it and establish a fairly consistent estimate of 8% to 10% of sperm from normal fertile men exhibiting a structural or numerical abnormality (Brandriff et al, 1985; Martin, 1985). In men of known fertility, the rate of aneuploidy was usually less than 2%. Interestingly, chromosome breaks were commonly reported, in as many as 15% of sperm from some men (Martin et al, 1983; Sloter et al, 2000).
The use of zona-free hamster oocytes to obtain metaphase-sperm chromosomes was valuable in establishing that aneuploidy and structural defects were commonly observed in sperm and that they varied in frequency between fertile men. However, the assay required that sperm be able to capacitate and penetrate zona-free oocytes, which precluded the analysis of sperm from men with most forms of severe male factor infertility, including oligozoospermia, asthenozoospermia, and severe capacitation defects. A second limitation of the assay was the low number of sperm that could be analyzed, which limited the statistical power of the analysis. Finally, the high costs of technician time and animal costs limited the potential for clinical use of the assay (Martin, 2007).
FISH Analysis— In the 1990s, FISH technology was first applied to the evaluation of sperm chromosome aneuploidy (Holmes and Martin, 1993; Templado et al, 1996; Van Hummelen et al, 1996). Using this technique, semen smears are air dried, and the sperm heads are slightly decondensed to facilitate hybridization with 2 to 5 fluorescent probes, either simultaneously or in subsequent hybridizations (Figure 2). The probes can be washed, and subsequent rehybridization with a second round of probes can allow analysis of 9 to 10 chromosomes.
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The accuracy of interphase FISH aneuploidy has generally been shown to be high in somatic cells, with sensitivities and specificities reported to be in the range of 98% to 100% (Shaffer and Bui, 2007). Although equivalent studies have not been performed in sperm, it is believed that the accuracy would be similar to somatic cells, although the condensed nature of sperm chromatin, even though it is gently decondensed prior to hybridization, may have some small effect on accuracy. The major limitations of standard FISH analysis of 5000 to 10 000 sperm, sometimes using 2 rounds of probes, remain the high cost and labor-intensive nature of the work. In our experience, manual microscopic analysis of a single sample typically requires 10 to 20 hours of technician time.
Automated FISH Analysis— Our laboratory has recently reported on the use of automated sperm FISH analysis to reduce the amount of technician time spent counting fluorescent signals when performing aneuploidy analysis (Carrell and Emery, 2007). Fluorescence-based automated cell analysis systems are somewhat commonly used in some clinical and research laboratories. Although the preparation and hybridization steps are identical to manual analysis, the automated system offers 3 major advantages to the analysis of signals. First, technician time is greatly reduced. Samples are loaded on an automated stage holder of the microscope, the software is initiated, and automated analysis and scoring can run unattended. The system can store images of cells for subsequent manual analysis, which is necessary, but the review of stored images can proceed much more quickly than microscopic, manual analysis. Additionally, the software can return the microscope to the actual slide location so that the sperm can be observed directly, rather than the processed image. Therefore, the system is not "fully automated;" it still contains a manual review of stored images but greatly reduces technician time spent analyzing samples.
The second advantage of the automated system is that the system allows better archival storage of images and data from each sample analyzed (Figure 3). Individual sperm images are routinely stored for each analysis performed, and our laboratory stores all abnormal sperm images on an auxiliary storage device. Additionally, the software allows for the potential application of data, such as cell measurements, shapes, and signal locations. These possible applications may facilitate some exciting research possibilities.
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Possible Future Technologies— Pellestor et al have authored a series of reports on the possible use of primed in situ (PRINS) fluorescence hybridization and peptide nucleic acid fluorescence in situ hybridization as possible alternatives to routine FISH (Pellestor, 2006; Pellestor and Charlieu, 1997). PRINS employs DNA polymerase to effect fluorescent primer extension in situ, whereas peptide nucleic acid hybridization employs synthetic DNA analogs (Pellestor, 2006; Pellestor et al, 2006). The authors report an improved specificity of this assay; however, further sperm studies are needed from other laboratories to evaluate the utility and potential benefits of these techniques over standard FISH.
Quantitative fluorescence polymerase chain reaction (QF-PCR) has been used to analyze aneuploidy. This technology employs PCR of highly polymorphic short tandem repeats (STRs) on the chromosomes to be analyzed using multiplex PCR with fluorescent primers, followed by automated analysis of fluorescent intensities to determine aneuploidy. QF-PCR is generally less expensive and time intensive than FISH; however, it has not been used in sperm. Separation of single sperm for this type of analysis is technically difficult, and the utility of data derived from large sperm populations has not been explored.
Comparative genome hybridization (CGH) has been looked to as a potential methodology to improve aneuploidy analysis of gametes and embryos due to the fact that it allows simultaneous evaluation of all chromosomes for copy number variations (CNVs) and has the resolution to look at the submicroscopic CNVs. Basically, CGH is performed by labeling the DNA of the patient with a given fluorochrome and the DNA of a healthy control with a different fluorochrome. Fragments of the 2 DNA samples are then hybridized to metaphase chromosomes of a control individual, and the competing fluorochromes can indicate relative copy number variations (aneuploidies or deletions) in the patient based on the intensities of the signal produced by the mixed probes (Kallioniemi et al, 1993, 1996). Modification of the technology to employ microarrays instead of metaphase chromosomes has facilitated the analysis of more than 200 000 discrete foci, greatly increasing the ability to identify small, submicroscopic microdeletions and improving the accuracy of aneuploidy analysis (Pinkel et al, 1998; Carter, 2007).
CGH technology is being used now in clinical and research protocols, including single-cell studies of oocytes and embryos (Delhanty, 2005; Fragouli et al, 2006; Sher et al, 2007). However, the procedure is expensive (microarray chips generally cost in the range of $500 or more) and time intensive (Swansbury, 2003). Like QF-PCR, the feasibility of single–sperm cell analysis has not been explored.
Recent studies have demonstrated that more than half of the variability between individuals' genomes is due to submicroscopic copy number variations of small regions of DNA in both coding and noncoding regions of the genome, and that these CNVs are responsible for some complex diseases, perhaps even more so than single-nucleotide polymorphisms (Freeman et al, 2006; Redon et al, 2006; McCarroll and Altshuler, 2007). There are currently more than 6000 known regions of CNV, and there are likely many more (Redon et al, 2006; Carter, 2007). CGH is currently one major technique for analyzing CNVs in a given individual (Carter, 2007). Whether this technology and this area of study move into the realm of gamete analysis remains to be seen.
Areas of Further Study and Explanation
Although the prudent use of sperm aneuploidy testing has been shown to be
clinically relevant and useful, the implementation of testing has not been
widely undertaken. Several reasons for this exist, including the need for a
better understanding of the genetic and cellular processes involved in the
generation of sperm aneuploidy, the identification of pathologies associated
with sperm aneuploidy to improve guidelines, clinical difficulties in the
interpretation of the assay results, and the expense of testing. None of these
hurdles are unique to sperm chromosome aneuploidy testing; however, the cost
and complexity of the assay have slowed the research needed to resolve the
underlying questions. However, recent studies have greatly advanced our
understanding of the possible mechanisms involved in the development of sperm
aneuploidy and the selection of patients for testing.
Understanding the Molecular Basis of Sperm Aneuploidy— Aneuploidy of gametes is intimately associated with improper recombination of homologous chromosomes during prophase I of meiosis (Topping et al, 2007). Prophase I of meiosis is divided into 4 stages, leptotene, zygotene, pachytene, and diplotene, which are defined by the morphology of the XY bivalent and the synaptic progression of the autosomal bivalents (Solari and Tres, 1970; Solari, 1980). During the leptotene stage, programmed double-strand breaks are formed, followed by alignment of homologous chromosomes and the initiation of synapsis in the zygotene stage. Recombination, the reciprocal exchange of genetic information between homologs at chiasmata, occurs during the midpachytene to diplotene stages (Figure 4). At the end of the diplotene stage, homologous chromosomes begin to desynapse, except for foci of reciprocal exchange.
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Several studies have shown significantly lower rates of meiotic recombination in infertile men (Gonsalves et al, 2004; Sun et al, 2005, 2005, 2007; Topping et al, 2006). In patients with obstructive azoospermia, there is a mean of 46.3 ± 6.3 crossover foci per spermatocyte compared with 40.4 ± 6.1 in men with nonobstructive azoospermia (NOA; Sun et al, 2005, Sun et al, 2005). Men with NOA also have a significant increase in the number of bivalents with no crossover foci, a precursor to abnormal segregation and aneuploidy (Gonsalves et al, 2004; Sun et al, 2005, Sun et al, 2005). There is also an increase in the number of gaps and splits in synaptonemal complexes in spermatocytes from men with NOA, and further studies are needed to ascertain their relevance (Gonsalves et al, 2004; Sun et al, 2004, 2005, 2005; Codina-Pascual et al, 2006; Topping et al, 2006). The effect of the gaps and splits is not yet well understood (Sun et al, 2005, Sun et al, 2005; Codina-Pascual et al, 2006), but reduced recombination has been shown to be a strong contributing factor in the production of aneuploid gametes (Hassold, 1998; Martin, 2005, 2006; Hall et al, 2006).
Faulty meiotic recombination can also contribute to infertility through the activation of meiotic checkpoints (Meier and Gartner, 2006). If the cell is unable to correct the error, it will trigger the initiation of apoptotic pathways, which in extreme cases can lead to global testicular failure (Roeder and Bailis, 2000; Gonsalves et al, 2004). The role of faulty recombination or checkpoint control in men with less severe forms of infertility than NOA has yet to be explored, but it is intriguing. Several studies have reported a link between sperm DNA damage, possibly induced through apoptotic processes, and sperm chromosome aneuploidy (Carrell et al, 2003; Schmid et al, 2003; Muriel et al, 2007). As is observed in the female, these checkpoint mechanisms may decline in fidelity with increasing age (Wyrobek et al, 2006).
Defects of recombination or abnormal checkpoint function may be due to myriad potential possibilities, including abnormal protein function resulting from gene mutation. Several meiosis-related gene knockouts have resulted in severe male factor infertility (Christensen and Carrell, 2002). Meiosis-related genes studied in human resequencing studies of infertile males have included SPO11 (Christensen et al, 2005) and SYCP3 (Miyamoto et al, 2003; Stouffs et al, 2005), and this is currently a field of ongoing study. However, no studies have studied either recombination or possible gene defects contributing to subtle recombination/segregation defects in infertile men with pathologies less severe than NOA, including patients with relatively normal semen quality but elevated aneuploidy.
Clinical Use of Aneuploidy Screening—
Sperm chromosome aneuploidy has been reported to be elevated in patients
with a wide range of clinical histories and pathologies (Table). Meaningful
use of the technology to assess sperm chromosome aneuploidy is dependent on
the quality of studies evaluating sperm aneuploidy and the subsequent prudent
application of the data to identify which patients may benefit from aneuploidy
testing. Martin (2007) has
recently provided an elegant review of the literature and guidelines for use
of the assay. Patients with the most likely risk of elevated sperm aneuploidy
include those with Klinefelter syndrome, structural rearrangements on
karyotype, severe morphologic defects, or nonobstructive azoospermia (Table).
Aneuploidy testing should be strongly considered in those patient
populations.
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Patients with a lower, but reasonable, chance of benefiting from sperm aneuploidy testing include those with unexplained recurrent pregnancy loss or unexplained repeated IVF failures. It appears that patients from those two groups have a moderate increase in the group's mean aneuploidy rate, derived from a small subset of patients with significantly elevated aneuploidy rates (Carrell et al, 2003; Petit et al, 2005). Men with moderately diminished semen quality may have a slight increase in aneuploidy, but it does not appear generally cost effective to perform aneuploidy testing in that group (Martin, 2007).
The Question of Relative Risk— Of course, the ultimate question of gamete aneuploidy testing is how the results translate to relative risk to the embryo. The question is imperative but difficult to answer due to a common list of problems, including the lack of prospective randomized trials, difficulties in translating animal studies to the human situation, and variations in techniques between laboratories. An additional factor that compounds aneuploidy studies is the fact that most studies employ 3 to 5 chromosome probes, a small fraction of the chromosome complement, and extrapolation is not straightforward due to the fact that some pathologies may be more commonly associated with aneuploidy of a certain set of chromosomes and other pathologies with a different set of chromosomes. For example, embryo lethality (miscarriage) is associated with different chromosomes (1, 15, 17, 21, 22), not the chromosomes most commonly analyzed (13, 18, 21, X, Y; Munne et al, 1998; Bahce et al, 1999). Additionally, one cannot simply multiply the aneuploidy rate for 5 chromosomes by a factor of 4.6 to obtain the risk for 23 chromosomes, since some sperm will have disomy or aneuploidy of multiple chromosomes, skewing the perception of affected and normal sperm.
Several retrospective studies have clearly linked prior birth of a child or conceptions with aneuploidy to elevated aneuploidy of the father's sperm (Blanco et al, 1998; Martinez-Pasarell et al, 1999; Carrell et al, 2001; Soares et al, 2001). Prospective studies also have shown an increased risk of aneuploidy in concepti and/or IVF failure in patients with elevated sperm aneuploidy (Martin, 1986; Nagvenkar et al, 2005). Gianaroli et al (2005) have reported that sperm aneuploidy is higher in sperm obtained surgically from men with NOA, and that blastomeres obtained from embryos derived in IVF cycles using those sperm have an elevated aneuploidy rate. Further prospective studies linking sperm aneuploidy directly with embryo aneuploidy rates are needed to obtain a better understanding of the relative risk of sperm aneuploidy to aneuploidy of concepti.
Cost of the Assay— The advances in automated testing described above open the door to reducing the high cost of screening sperm for chromosome aneuploidy by lowering the technician time involved in analyzing a given specimen. However, 2 significant cost hurdles remain. First, the hardware and software are expensive (>$100 000). This may limit the use of the technology to cytogenetic or andrology laboratories using the technology for other clinical or research projects, the collaboration of andrology and cytogenetic laboratories, or the use of large institutional core facilities. Second, fluorescent probe costs remain expensive (>$100 per 5 probes).
Although the possibility of reducing the costs of the assay through reductions in the price of the equipment or supplies or by the implementation of new technologies, such as CGH, remains a possibility, it is likely that aneuploidy screening will remain expensive in the near future. The cost-benefit ratio of the assay will depend on the future outcome of large-scale, prospective, randomized studies and further animal studies.
Conclusions
The development of the chromosomal basis of heredity quickly led to an
understanding that variations in the number of chromosomes in a genome were
responsible for severe anomalies in the individual, miscarriage, or early
embryo lethality (Jacobs et al,
1959). We are now beginning to understand that sperm chromosome
aneuploidy is elevated in many types of infertility, and it not only increases
risk to offspring but also affects infertility therapy outcomes
(Gianaroli et al, 2005;
Petit et al, 2005). Therefore,
the potential effects of sperm chromosome aneuploidy in infertile men are
severe and relevant to some types of infertility or recurrent pregnant loss.
Diagnosis of an elevated risk of sperm chromosome aneuploidy may reduce risk
to the offspring, and in some cases reduce the high financial and emotional
expense of repeated IVF failure.
The analysis of sperm chromosome aneuploidy by FISH technology has greatly improved our understanding of pathologies associated with elevated risk of aneuploidy. Automated analysis technology is a first step in the attempt to simplify the testing of sperm aneuploidy, and ultimately reduce the cost of testing. The refinement of CGH or other developing technologies may further benefit this study by increasing the quality of data (the full complement of chromosomes would be analyzed) and by potentially reducing costs. Further studies on submicroscopic copy number variations obtained by CGH or similar techniques may ultimately provide another clinically important aspect of copy number variation and its effect on fertility and embryogenesis.
The clinical implementation of sperm chromosome aneuploidy has been hampered by the high cost of testing and a paucity of data to validate the benefit of testing and provide clinical guidelines of which patients should be evaluated. Fortunately, those data are now becoming available and demonstrate that prospective testing may be prudent in cases of severe male infertility, including NOA, especially if the patient has prior cases of failed IVF/ICSI. Prospective testing should always be prospectively performed in cases of severe morphologic defects, such as macrocephaly, round head–only syndrome. Sperm aneuploidy testing may also be beneficial in cases of unexplained recurrent pregnancy loss and repeated IVF failure.
Footnotes
* Andrology Lab Corner welcomes the submission of unsolicited
manuscripts, requested reviews, and articles in a debate format. Manuscripts
will be reviewed and edited by the Section Editor. All submissions should be
sent to the Journal of Andrology Editorial Office. Letters to
the editor in response to articles as well as suggested topics for future
issues are encouraged. 
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